BackgroundHepatocellular carcinoma (HCC) is the most common primary liver malignancy. Phloretin (PH) possesses anticancer, antitumor, and hepatoprotective effects, however, the effects and potential mechanisms of phloretin remain elusive.MethodsFive HCC cells were tested in vitro for sensitivity to PH, Sorafenib (Sor) or both and the apoptosis, signal transduction and phosphatase activity were analyzed. To validate the role of SHP-1, we used PTP inhibitor III and SHP-1 siRNA. Further, we used purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants to study the PH efficacy on SHP-1. The `in vivo studies were conducted using HepG2 and SK-Hep1 and Sor resistant HepG2SR and Huh7SR xenografts. Molecular docking was done with Swiss dock and Auto Dock Vina.ResultsPH inhibited cell growth and induced apoptosis in all HCC cells by upregulating SHP-1 expression and downregulating STAT3 expression and further inhibited pAKT/pERK signaling. PH activated SHP-1 by disruption of autoinhibition of SHP-1, leading to reduced p-STAT3Tyr705 level. PH induced apoptosis in two Sor-resistant cell lines and overcome STAT3, AKT, MAPK and VEGFR2 dependent Sor resistance in HCCs. PH potently inhibited tumor growth in both Sor-sensitive and Sor-resistant xenografts in vivo by impairing angiogenesis, cell proliferation and inducing apoptosis via targeting the SHP-1/STAT3 signaling pathway.ConclusionOur data suggest that PH inhibits STAT3 activity in Sor-sensitive and -resistant HCCs via SHP-1–mediated inhibition of STAT3 and AKT/mTOR/JAK2/VEGFR2 pathway. Our results clearly indicate that PH may be a potent reagent for hepatocellular carcinoma and a noveltargeted therapy for further clinical investigations.Graphical abstract Electronic supplementary materialThe online version of this article (10.1186/s12964-019-0430-7) contains supplementary material, which is available to authorized users.
Costunolide is known to possess anti-inflammatory and antitumor activity, but its role in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. We aimed to investigate the effects of costunolide on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and costunolide (5, 10 and 20 mg/kg/day) was administered for 14 days through installed cannula. The implants collected at day 14 post-implantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen, which were used as indices for angiogenesis, neutrophil and macrophage accumulation, and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Costunolide treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition, and the levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor (TNF)-α and transforming growth factor (TGF-β). Regulatory function of costunolide on multiple parameters of the main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic benefit underlying the anti-angiogenic actions of costunolide.
Background: With the emergence of resistance to FDA-approved inhibitors of androgen receptor (AR) signaling in prostate cancer, AR remains a viable target, engaged in the regulation of processes of pathological importance. CRPC tumors adapt the PI3K/AKT survival pathway to escape ADT. Thus, co-targeting AR and PI3K/AKT signaling is more effective therapeutic means for CRPC patients. Phloretin (PH), is a polyphenolic compound, found in apples, cider etc. It is known to possess anticancer and anti-angiogenetic activity. However, it`s effect against CRPC cells and the underlying mechanism are still unknown. Experimental procedure: Ten human PCa cell lines were tested in vitro for sensitivity to the PI3K/AKT inhibitor LY294002; enzalutamide (ENZ); PH; LY294002 + PH; ENZ + PH and LY294002 + ENZ + PH. In vivo studies were conducted using VCaP, 22Rv1, MR49F xenografts and LuCaP and 136CR PCa PDX tumors. Molecular docking was done with AutoDock Vina program. CSF Chimera and Ligplot programs were used for analysis of ligand and proteins interactions. Results: LY294002; ENZ; PH; LY294002 + PH; ENZ + PH and LY294002 + ENZ + PH inhibited in vitro growth of 7 of 10; 9 of 10; 9 of 10; 9 of 10; 9 of 10; 10 of 10 PCa cell lines, respectively, with increased sensitivity under androgen depletion. PH inhibited tumor growth in VCaP, 22Rv1, MR49F, MR49C xenografts and LuCaP and 13CR PCa PDX in a dose-dependent manner. Further, dual combination of ENZ + PH was more effective than LY294002 + PH in inhibiting tumor growth, whereas LY294002 + ENZ + PH diminished the tumor growth (P<0.005) and demonstrated a longer disease specific survival. PH alone inhibited the AR-DNA interaction directly or by interfering with AR dimerization and inhibited AR-V7 expression and transcriptional activity. Further, it blocked the R1881 induced expression of AR-target genes kallikrein-related peptidase 3 (KLK3, also known as PSA); transmembrane protease, serine 2 (TMPRSS2); and FK506 binding protein 5 (FKBP5), glucocorticoid receptor (GR). In LuCaP PCa PDX tumors, PH administration decreased TV (P=0.021), proliferation (p=0.0024), PSA (p<0.005) and decreased AR signaling and nuclear glucocorticoid receptor (nGR) localization. Computer aided molecular docking data shows the binding affinity and ligand efficiency scores of PH in following chronological order: AR > AKT1 > GR > PI3K. Conclusion: Our studies suggested triple combination improved the efficacy of ENZ and PH. PH could be promising candidates for prevention of CRPC. This pre-clinical synergy provides a strong rationale for clinical evaluation of this combination. Citation Format: Sarita Saraswati, Abdulqader A. Alhaider, Abdelgalil M. Abdelgadir. Dual targeting of PI3K/AKT and AR pathway by combination therapy with phloretin in pre-clinical and patient derived xenografts of enzalutamide-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 257.
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